Abstract Homologous recombination deficiency is prevalent in breast cancer up to a level of ~25%. Large-scale alterations to the genome have been observed in these tumors, but if double-strand junctions are sequenced in addition, it is possible to categorize these tumors into upstream and downstream defects in the DNA repair pathway. We assert that there fundamentally different patterns of genome instability for double-strand break repair. One is focused on the function of the BRCA1-BRCA2 pathway, where alterations in function are rather frequent in breast cancers. Although traditionally perceived as equivalent, there is evidence to demonstrate that downstream alterations that are BRCA1-like may have genomic and functional differences from those that are BRCA2-like. Conversely, the upstream defects are focused on sensing DNA damage, which is another way to suppress cancer formation. Our hypothesis is that different types of DNA repair defects result in the utilization of distinct back-up DNA repair mechanisms, which themselves result in specific genomic signatures and sensitivity to different therapeutic agents. Hence, we posit that upstream defects are best targeted by the use of replication checkpoint inhibitors, but that BRCA defective tumors are best treated by targeting the backup pathway, such as PARP-inhibitors or new agents beyond PARP-inhibitors. The goal of the first aim is to apply the current genomic landscape tests of HR-deficiency and determine which method predicts most accurately the type of homologous recombination DNA repair defect. The ultimate goal is to devise a taxonomy based on the genomics features of homologous recombination DNA repair-deficiency, in addition to target gene mutations, which will ultimately guide therapeutic options. The second aim is to generate genetically engineered cell lines to understand the developmental drivers of the genomic landscape changes. In addition, we will use these cells to test new synthetic lethal approaches to target specific subsets of breast cancers with distinct types of homologous recombination DNA repair defects. The third aim consists of human clinical trials either being conducted at Memorial Sloan Kettering Cancer Center or elsewhere, where we are conducting the trial or leading the analysis of the clinical bio-specimens for correlative study analyses. We will study the impact of the PARP-inhibitor olaparib in patients who are BRCA1/2 wild-type but harbor a germline and/or somatic genetic alteration affecting homologous recombination DNA repair-related genes. We will extend our studies to also consider the combined effects of radiotherapy in combination with either ATR- inhibitors or PARP-inhibitors. The ultimate goal of this project is to personalize the treatment of breast cancer patients whose tumors display homologous recombination DNA repair-related defects according to their genetic and genomic features, seeking to substantially improve the outcome of these poor prognosis patients and direct the deployment of therapeutic agents either already approved (e.g. olaparib) or already in clinical trials (e.g. ATR-inhibitors).